Status epilepticus (SE) is a life-threatening condition in which the brain is in a continuous state of seizure. Rapid seizure control is essential to reduce morbidity and mortality. Benzodiazepines (BZDs), such as diazepam (DZP), which enhance GABAA receptor-mediated inhibition, are the first-line therapy for the treatment of SE. Despite their effectiveness, at least 35% of patients with generalized convulsive SE are refractory to BZDs. In addition, evidence from clinical and animal studies indicates that successful treatment of SE with BZDs is negatively affected by seizure duration. Pharmacoresistance to BZDs develops rapidly after the initiation of SE. Indeed, rodent studies have shown an approximate 9-10 fold decrease in the efficacy of diazepam at terminating prolonged SE (45 minutes after onset). The development of pharmacoresistance during SE is due in part to a selective decrease in benzodiazepine-sensitive populations of GABAA receptors, leaving a population of receptors that is not modulated by these drugs. Specifically, BZDs only act at GABAA receptors containing γ subunits and SE decreases surface expression of GABAA receptors containing γ2 subunits.
As such, a need exists for an improved method of treating and/or preventing SE that minimizes the development of pharmacoresistance during treatment.